The epidemic is not over during the dog days of summer, and it will cause more trouble in autumn and winter?

Thousands of years ago, humans noticed that certain diseases would become prevalent in certain seasons. Is it because of the climate/weather? Is it because of the patterns of human activities? Or is it because the immune system itself is sometimes strong and sometimes weak? This ancient mystery has not been solved so far. And whether COVID-19 also shows seasonal characteristics, it will take time to give an answer.

Written by | Idobon

In early 2020, during a high-incidence flu season, the novel coronavirus also spread wildly and spread all over the world. Since the outbreak, people have been hoping that the novel coronavirus will gradually disappear as the temperature rises, just like the flu. In February, US President Trump repeatedly mentioned a theory that the novel coronavirus will be killed when the weather warms up in April. However, to date, the number of newly confirmed cases in the United States has exceeded 70,000 per day.

More than 2,500 years ago, humans discovered that many infectious diseases are more common in certain seasons, such as influenza, which is often prevalent in cold and dry winters. But the seasonal phenomenon of disease has not been well explained so far. Andrew Loudon, a chronobiologist at the University of Manchester, said that this problem is very difficult to study because it may take two or three years to verify the "seasonal hypothesis of disease", and only this one experiment can be done during the postdoctoral period, which is quite detrimental to one's career. More importantly, this field is full of confounding variables, and researchers are very likely to fall into the trap of spurious correlations.

In 2018, Micaela Martinez, an infectious disease ecologist at Columbia University, published a study in PLOS Pathogens[1], finding that at least 68 infectious diseases are seasonal, but their epidemic cycles are not synchronized and vary depending on the epidemic area:

Except in tropical areas, respiratory syncytial virus (RSV) is most common in winter, and chickenpox is most common in summer. In the United States, rotavirus is most common in the Southwest from December to January, and in the Northeast from April to May. Genital herpes spreads throughout the country in spring and summer, while tetanus has to wait until midsummer. Gonorrhea starts to spread in summer and fall, and pertussis is more common from June to October. In China, syphilis is more contagious in winter, while typhoid surges in July. In India, hepatitis C is most rampant in winter, while in Egypt, China, and Mexico, it is rampant in spring and summer. Guinea worm disease and Lassa fever in Nigeria and hepatitis A in Brazil are clearly associated with the dry season.

The following table is based on US health record data. The size of the circle represents the proportion of the number of people infected with the disease this month to the annual number of infections. Many of the data in the table are historical data, because after the emergence of vaccines, the number of infections of many diseases has been very small or even zero.

The calendar of epidemics

Source | https://www.sciencemag.org/news/2020/03/why-do-dozens-diseases-wax-and-wane-seasons-and-will-covid-19 (Original image can show detailed data)

There are many factors that cause seasonal epidemics of infectious diseases. The simplest and most intuitive one is diseases spread by insects. For example, African sleeping sickness, chikungunya, dengue fever, and river blindness all spread during the rainy season when mosquitoes are abundant.

However, for other infectious diseases, it may be impossible to find a cycle at all, let alone figure out the cause. Neal Nathanson, a retired virologist at the University of Pennsylvania, said: "The most incredible thing is that you can always find a virus that will be prevalent every month in the same place and under the same environment." This means that human activities - such as students returning to school and staying at home in winter - are not the root cause of the epidemic. This is because most viruses are transmitted between children. If the seasonality of infection is completely affected by human behavior, then most infectious diseases should be prevalent in the same month.

Nathanson suspects that the ability of viruses to survive outside the human body is a more important factor than human activity. Some viruses have not only a capsid that encloses their genetic material, but also an envelope made of lipids. The envelope facilitates the interaction between the virus and the host cell and helps the virus evade the attack of the immune system. However, the envelope also brings disadvantages to the virus: Envelope viruses are more fragile and have a harder time surviving the hot and dry summer.

A report in Scientific Reports in 2018 supports Nathanson's hypothesis. In the respiratory samples of 36,000 patients collected in the past seven years, Sandeep Ramalingam, a virologist at the University of Edinburgh in the UK, collected nine viruses, some with envelopes and some without. After analysis, Ramalingam found that the enveloped viruses had a fairly definite seasonality.

Like influenza viruses, respiratory syncytial virus and human metapneumovirus have envelopes, are prevalent in winter, and appear no more than four months a year. Rhinoviruses, which cause the common cold, do not have envelopes and, of course, do not favor winter - respiratory samples show that rhinoviruses are active on 84.7% of the days of the year, and they become prevalent when students return to school after winter and summer vacations. Another common virus that causes the common cold, adenoviruses, also do not have envelopes and are active for more than half a year.

Ramalingam's team also studied the relationship between viral load and daily weather changes. When the relative humidity changes by no more than 25% within 24 hours, the influenza virus and respiratory syncytial virus load is the largest; when the humidity changes dramatically, the lipid envelope becomes more fragile and the viral load decreases.

Climate geophysicist Jeffrey Shaman believes that what really matters is absolute humidity rather than relative humidity. The former refers to the total amount of water vapor in a unit volume of air, while the latter refers to the degree to which the air humidity is close to saturation. His collaborative research with Harvard University epidemiologist Marc Lipsitch pointed out that the decline in absolute humidity can more clearly explain why the flu season in the continental United States is in winter than relative humidity and temperature - the absolute humidity drops more sharply in winter because the cold air contains less water vapor.

However, we still don't know why some viruses are so easily affected by absolute humidity. Osmotic pressure, evaporation rate and pH value may affect the survival probability of viral capsids, but there is no answer to the mechanism of action.

The coronavirus also has an envelope. Could it also be more vulnerable in the spring and summer when humidity rises? Unfortunately, the SARS coronavirus and the MERS coronavirus leave us no clues. SARS exploded in late 2002 and then disappeared in the summer of the following year. MERS, which jumped from camels to humans, has only had small outbreaks in hospitals but has never spread as widely as the coronavirus. Both viruses spread too quickly and over small areas to show seasonal cycles.

In contrast, four human coronaviruses that can cause the common cold are more telling. Kate Templeton, a molecular biologist at the University of Edinburgh, investigated 11,611 respiratory samples from 2006-2009 and found that three of them can cause typical winter epidemics, while they are almost undetectable in summer. The behavior of these three coronaviruses is very similar to that of influenza.

But this does not mean that the new coronavirus is also true. Singapore now has more than 40,000 confirmed cases (there were less than 200 cases in March); the new coronavirus epidemic is now serious in the southwestern states of the United States, especially Arizona. All of this shows that the new coronavirus can undoubtedly spread in warm and humid environments. There are currently two opposite conclusions: First, looking at the epidemic spread in mainland China, covering 19 provinces, municipalities and autonomous regions, from cold and dry to hot regions, the transmissibility of the new coronavirus has not weakened. Second, the new coronavirus can only spread stably in areas around the world with temperatures between 5°C and 11°C and relative humidity between 47% and 79% [2]. The conclusions of these two studies are contradictory.

All in all, there is a balance between environmental factors and the immune system of the population. Other coronaviruses have existed in human society for a long time, and a part of the population has developed resistance, which may help prevent the spread of infectious diseases, especially when the natural environment is not conducive to the spread of the virus. However, this situation does not apply to COVID-19. Martinez said that even if the new coronavirus has a seasonal cycle, even if it becomes inactive in spring and summer, as long as there are enough susceptible people gathered together, the new coronavirus can resist for a long time. Therefore, when Trump frequently claimed that the epidemic would subside in April (of course, we all know that he was slapped in the face now), many researchers felt that this was unreliable. Lipsitch wrote in his blog: Even if the new coronavirus is less active and the epidemic is really slowed down, it will not be enough to stop the spread of the virus.

Currently, most theories focus on the relationship between pathogens, the environment, and human behavior. For example, influenza is prevalent in winter, which may be due to low humidity, low temperature, more crowded crowds, changes in diet, and changes in vitamin D levels. However, epidemiologist Scott Dowell believes that these factors are not sufficient to explain the relationship. In 2001, he published a widely cited paper [3], proposing an unverified "photoperiod hypothesis": the immune system's resistance to different infectious diseases varies with the seasons, which is related to the amount of light the human body receives.

Dowell's hypothesis inspired Martinez. She asked the subjects to come to the clinic regularly at four time points: the vernal equinox, summer solstice, autumnal equinox, and winter solstice, to evaluate the immune system and other physiological changes during the day. She did not expect the immune system to show simple time characteristics: weak in winter and strong in summer. However, by counting the number of different cells of the immune system, evaluating metabolites and cytokines in the blood, deciphering the fecal microbiome, and measuring hormone levels, Martinez hopes to find a season that can "reconstruct" the immune system-in other words, this particular season can make some cells more in specific locations and others less, thereby affecting the body's susceptibility to pathogens.

Animal studies support the hypothesis that the immune system fluctuates with the seasons. Barbara Hall, an ornithologist at the University of Groningen in the Netherlands, studied European thrushes. They collected blood samples from birds several times a year and found that the immune systems of these thrushes were more active in the summer and more suppressed and stable in the autumn, which may be because the migration in the autumn is quite energy-consuming.

Randy Nelson, an endocrinologist at West Virginia University, believes that the seasonal ups and downs of the immune system are dominated by melatonin. Melatonin secreted by the pineal gland not only regulates the circadian rhythm, but also the seasonal "biological calendar." As the nights get longer, the pineal gland secretes more melatonin. "The cells say: Oh, I see a little more melatonin, I know, it's a winter night." Nelson conducted experiments on diurnal Siberian hamsters (note that ordinary mice are nocturnal) and found that regulating melatonin or changing the light pattern can affect the hamster's immune response, and the impact is as high as 40%.

The human immune system also seems to have an innate circadian rhythm. In 2016, the University of Birmingham in the UK tested the flu vaccine on 276 adults, randomly selecting half of them to receive the vaccine in the morning and the other half in the afternoon. The results showed that the antibody response produced by those who received the vaccine in the morning was significantly stronger[4].

Even more amazing is that there is also evidence that the human immune system changes with the seasons. In 2015, researchers at the University of Cambridge collected more than 10,000 blood and tissue samples from Europe, the United States, Gambia, and Australia and found that about 4,000 immune-related genes were expressed differently with the seasons. In a group of German samples, nearly a quarter of immune genes were expressed in white blood cells with the seasons. Some genes are not expressed when the human body is in the southern hemisphere, but when a person comes to the northern hemisphere, they turn on their expression, and vice versa [5].

However, the first author of the study, immunologist Xaquin Castro Dopico, also pointed out in the paper that it is not clear how these large-scale and general changes in the immune system affect the body's fight against pathogens. In addition, some changes may be the result of infection rather than the cause. Although the research team tried their best to exclude samples from subjects with acute infectious diseases, some were inevitably mixed in.

More importantly, seasonal changes in the immune system are not enough to explain the seasonality of the disease, which is much more complex and has more variables. As Nathanson said: These infectious diseases are not synchronized at all. He doubts that seasonal changes in the immune system are enough to cause such obvious asynchrony.

Martinez's experiments have collected data and have not found evidence of seasonality in the immune system. However, she did find that a subset of white blood cells, which play a central role in the immune system, respond more vigorously at certain times of the day. However, Martinez is deeply concerned that artificial light may disrupt the circadian rhythm given to us by evolution, ultimately having unpredictable effects on disease susceptibility.

In his 2001 paper, Dowell suggested that we could use “experiments of nature” to gain insight into factors that influence disease seasonality. For example, people from the northern and southern hemispheres meet and socialize on cruise ships, adapting to different seasonal cycles but facing the same pathogens. In the case of the Diamond Princess COVID-19 outbreak, researchers could consider analyzing infection rates among passengers from different regions to see if they are the same.

Although the COVID-19 pandemic is currently a global emergency and has attracted the most attention, it is equally important to study why various infectious diseases sometimes peak and sometimes die out during the year. Understanding this issue can provide us with new ideas for preventing and treating COVID-19. Understanding the so-called "seasonality" can also help us monitor diseases and determine the time for vaccination. "If we can figure out why the flu doesn't become popular in the summer, it will be much more useful than any flu vaccine," Dowell said.

References

[1] Martinez ME (2018) The calendar of epidemics: Seasonal cycles of infectious diseases. PLoS Pathog 14(11): e1007327. https://doi.org/10.1371/journal.ppat.1007327

[2] https://gvn.org/enhanced-model-for-monitoring-zones-of-increased-risk-of-covid-19-spread/

[3] Dowell SF (2001). Seasonal variation in host susceptibility and cycles of certain infectious diseases. Emerging infectious diseases, 7(3), 369–374. https://doi.org/10.3201/eid0703.010301

[4] Long, JE, Drayson, MT, Taylor, AE, Toellner, KM, Lord, JM, & Phillips, AC (2016). Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial. Vaccine, 34(24), 2679-2685.

[5] Dopico,

The main reference source of this article: https://www.sciencemag.org/news/2020/03/why-do-dozens-diseases-wax-and-wane-seasons-and-will-covid-19